Role of Zinc in the Pathogenesis of Attention-Deficit Hyperactivity Disorder
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The dopamine transporter is regulated by zinc (Zn2+), which directly interacts with the transporter protein as a potent non-competitive blocker of substrate translocation (dopamine transport inward and outward). The fact that dysfunction of the dopamine transporter is involved in the pathogenesis of attention-deficit hyperactivity disorder (ADHD) is interesting in the context of studies that suggest the involvement of zinc deficiency in patients with ADHD. In this article, we present a hypothesis exploring the causative mechanism of zinc deficiency in ADHD and why zinc might be beneficial as a supplementary medication and/or adjunct to psychostimulants (methylphenidate, amfetamine) in zinc-deficient ADHD patients. The hypothesis is based on published in vitro observations that the human dopamine transporter contains a high-affinity zinc binding site (His-193, His-375, Glu-396) on its extracellular face that modulates transporter function, and in vivo studies suggesting that response to stimulants is reduced in zinc-deficient ADHD patients. It seems likely that zinc supplementation in zinc-deficient ADHD patients improves the binding status of insufficiently occupied zinc binding sites on the dopamine transporter. We propose to test our hypothesis by recruiting zinc-deficient ADHD patients who will undergo positron emission tomography with the 11C-raclopride displacement method to investigate whether zinc increases extracellular dopamine levels.
PL has received honoraria for educational talks in the last 5 years from Eli Lily, Otsuka and AstraZeneca. MH has nothing to declare.
Both authors contributed equally to the manuscript (other contributors, including medical writers and editors, were not involved). No sources of funding were obtained to assist with the preparation of this article.
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